Skin is a physical barrier to the environment. Alteration of the barrier properties and actual damage to this barrier cause skin aging signs and various other skin conditions and disorders.
The epidermis and the dermis, separated by the basal membrane, constitute the cutaneous covering on the hypoderm. The epidermis is the most superficial layer of the skin and provides its resistance and impermeability. Alteration of this layer will affect negatively the appearance of the skin.
Aging of the skin is a complex biological process which is mediated by a combination of the effects of time (intrinsic aging) and environmental factors (extrinsic aging) on cellular and extracellular infrastructure.
As a result of skin aging, deep changes happen at both dermis and epidermis levels. The amount of water held by the epidermis decreases, skin keratinocytes renewal rate slows down, glycosaminoglycans (GAGs) production decreases, renewal of collagen fibers diminishes and the extracellular matrix becomes disorganized. All those events conduct to the typical apparition of wrinkles and fine lines, thinning of the skin, and loss of firmness, elasticity and moisture.
Over time, dead skin cells do not shed as quickly and turnover of new skin cells may decrease slightly. The skin cells in the bottom layer of the epidermis (stratum basal) constantly multiply through cell division, forming new keratinocytes. This regenerative process is called skin cell renewal. As we age, the rate of skin cell renewal decreases, causing cells to become stickier and to not shed as easily. As a result of cell renewal decreasing, the skin becomes thinner and more susceptible to environmental damages. Eventually, the skin appears dull and rough in texture.
With age, the synthesis of GAGs decreases, affecting moisture level in the dermis, collagen synthesis and cellular proliferation. Glycosaminoglycans are associated with proteins to form proteoglycans molecules. In the dermis, proteoglycans interact with collagen fibers allowing their optimal orientation, good stability of the dermis structure and skin firmness.
Within the skin, the structural protein called collagen, found in the dermis, provides a mesh-like framework of support and strength for the skin. As we age, collagen production decreases and collagen fibers degrade at a faster rate than in earlier years. This results in an overall decrease in the amount of collagen in the dermis. Areas with less support begin to cave in and wrinkles begin to form. Thus, collagen becomes less soluble, thinner, and sparser in intrinsically aged skin. The ratio of type III to type I collagen is reported to increase with age. Histologically, young collagen is randomly organized into a meshwork of loosely interwoven bundles. Age leads to a loosening within these bundles and straightening of collagen fibers, increasing the skin's tensile strength. Elastin is a long-lived protein in human skin; it appears to accumulate damage with age and sun exposure. New elastin is synthesized in greater quantities in aged skin, but it is thought that this synthesis results in abnormally structured elastin. Also, elastin degradation does not appear to keep pace with new synthesis in aged skin. This results in massive accumulations of elastoic material, especially in photoaged skin. The abnormal structure of this elastin prevents it from functioning as it does in young skin.
Studies of primary and tertiary skin protein structures in aged skin reveal an environment unfriendly to water, with an overall increase in hydrophobic amino acids and greater folding such that aliphatic residues are more concealed from water. Also, although total amounts of GAGs appear to be increased in aged skin, these are abnormally localized on the elastoic material in the superficial dermis; thus, they are unable to bind water as well as if they were scattered appropriately throughout the unfractionated dermis. Hence, it is not surprising that, although aged skin contains increased amounts of water, most of this water is bound to itself in tetrahedral form, rather than being bound to proteins and GAGs as it is in young skin. These factors together likely contribute to increased xerosis and withered appearance of aged skin. While it tends to be an accepted assumption that lipid content decreases with age, quantitative studies are conflicting. Some indicate a marked age-related decrease in skin lipids, at least up to age 50 years, while others indicate little or no relationship.
Cutaneous tissue repair aims at restoring the barrier function of the skin. To achieve this, defects need to be replaced by granulation tissue to form new connective tissue, and epithelial wound closure is required to restore the physical barrier. Different wound-healing phases are recognized, starting with an inflammation dominated early phase giving way to granulation tissue build-up and scar remodeling after epithelial wound closure has been achieved. In the granulation tissue, mesenchymal cells are maximally activated; cells proliferate, and synthesize huge amounts of extracellular matrix. Epithelial cells also proliferate and migrate over the provisional matrix of the underlying granulation tissue, eventually closing the defect. There is ample evidence that keratinocytes stimulate fibroblasts to synthesize growth factors, which in turn will stimulate keratinocyte proliferation in a double paracrine manner. Moreover, fibroblasts can acquire a myofibroblast phenotype under the control of keratinocytes. This depends on a finely tuned balance between a proinflammatory or a transforming growth factor (TGF)-β-dominated environment. As the phenotype of fibroblasts from different tissues or body sites becomes better defined, we may understand their individual contribution in wound healing in more detail and possibly explain different clinical outcomes.
To date, the best known way to solve these age-related problems is retinol. Retinol belongs to the retinoids family, a class of chemical compounds that are related chemically to vitamin A. Retinol is easily absorbed by the epidermis and is known to have a broad spectrum of biological activities. More specifically, retinol increases cellular renewal in the basal layer of the epidermis, normalizes cellular differentiation and regulates the keratinization process. It also has an effect on the dermis. Studies on humans have shown that retinol increase the quantity of collagen in the dermis. It also has been shown to increase skin elasticity and to reduce the depth of wrinkles on women. Presently, retinol represents the most effective non-surgical treatment approach on the market for counteracting skin aging and wrinkles. Topical retinoids have been proven to prevent and repair clinical features of photoaging; these processes are facilitated by an ability to prevent loss of collagen from, and stimulate new collagen formation in, the papillary dermis of sun-exposed skin. Emerging evidence indicates that intrinsic, chronological aging of the skin shares several mechanistic features with photoaging. Indeed aged skin is characterized by retinoid sensitivity and is probably reparable by application of topical retinoids.
Despite their numerous benefits, the utility of topical retinol as a treatment for improving the appearance of aged and photodamaged skin, is limited by erythema, scaling/dryness, burning/stinging and irritation that occurs during the early phases and long term use of facial retinization. These concerns are often leading to the withdrawal and failure of the retinol-associated treatment.
Therefore, there remains a need to develop new approaches for the prevention and/or treatment of skin-aging signs and other skin conditions and disorders such as scar healing.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.